Is GLIS3 p.Pro451Ser (c.1351C>T) pathogenic?

GLIS3 p.Pro451Ser (c.1351C>T) is classified Uncertain significance in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-25). AlphaMissense: likely benign (0.0757); Ultra-rare (popmax 0.0364%, mid); Associated with Inborn genetic diseases.

What condition is associated with GLIS3 p.Pro451Ser (c.1351C>T)?

GLIS3 p.Pro451Ser (c.1351C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GLIS3 p.Pro451Ser (c.1351C>T) in the general population?

GLIS3 p.Pro451Ser (c.1351C>T) is ultra-rare (popmax 0.0364%, mid) (gnomAD).

What do computational predictors say about GLIS3 p.Pro451Ser (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

GLIS3 p.Pro451Ser

c.1351C>T · VCV3520582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -11.50	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	19.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P296S vs ClinVar P451S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0364% Middle Eastern · 2/5,494 alleles

Filtering AF 0.00637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00263%

Overall 0.000903% 14/1,550,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0364%	2,747
African / African-American	0.00815%	12,265
East Asian	0.00453%	22,071
Remaining individualsnot grpmax-eligible	0.00336%	29,771
South Asian	0.00123%	81,010
European (non-Finnish)	8.71e-05%	1,147,700

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GLIS3
Protein: p.Pro451Ser
Coding: c.1351C>T
MANE Select: NM_001042413
Type: single nucleotide variant
Location: chr9:4118127 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95

Full GLIS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GLIS3 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
GLIS3 p.Ala784Pro Uncertain significance ★★ ⚠ same condition
GLIS3 p.Arg637Cys Uncertain significance ★★ ⚠ same condition
GLIS3 p.Arg663Gln Uncertain significance ★★ ⚠ same condition
GLIS3 p.Asp310Asn Uncertain significance ★★ ⚠ same condition
GLIS3 p.Cys676Phe Uncertain significance ★★ same condition
GLIS3 p.Gly385Ser Uncertain significance ★★ ⚠ same condition
GLIS3 p.Gly491Arg Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/glis3-p-pro451ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown